Rivastigmine Patch in Veterans With Cognitive Impairment Following TBI

Traumatic brain injury (TBI) represents one of the most significant health risks related to
military duty; rapidly becoming the "signature injury" of the Iraq and Afghanistan
conflicts. TBI patients often experience multiple cognitive problems, with disturbances in
memory, attention, and executive functions among the most common. Disturbances in memory as
well as attention are particularly problematic, as disruption of these relatively basic
cognitive functions may exacerbate or cause additional disturbances in executive function,
communication and other more complex cognitive domains. These cognitive deficits, especially
when memory is affected, significantly impact day-to-day functioning and are the source of
lingering disability and distress to the affected individuals. However, despite advances
made in TBI care, treatment of cognitive deficits in TBI lag behind, forcing clinicians to
provide treatment without the guidance of evidence-based scientific data. This proposal aims
to begin the process of providing clinicians with evidence-based guidelines for
pharmacological management of Veterans with TBI suffering from persistent cognitive deficits
following their injuries. This aim will be accomplished by conducting a clinical trial in
Veterans suffering from moderate to severe posttraumatic memory impairment following TBI.
Specifically, this proposal will evaluate the efficacy and safety of rivastigmine
transdermal patch, an intermediate-acting cholinesterase inhibitor, in this population.

The investigators hypothesize that rivastigmine transdermal patch will be more effective
than, and equally safe as, placebo in the treatment of moderate to severe posttraumatic
memory impairment in Veterans with TBI when tested in a randomized, multi-site, parallel
design, placebo-controlled trial, at a 12-week endpoint. The exploratory hypothesis states
that compared to placebo, rivastigmine patch will be more effective and equally safe in the
treatment of patients who will continue in a randomized, placebo-controlled phase for a
total of 26 weeks. To test these hypotheses we will evaluate the effect and the safety of
rivastigmine 9.5 mg/24 hours (10cm2) transdermal patch in 138 Veterans who meet or exceed
the criteria for closed, non-penetrating, mild TBI and who present at baseline with moderate
to severe memory impairment. Memory impairment will be defined as a Total Recall index
(Trials 1-3) of the Hopkins Verbal Learning Test-Revised (HVLT-R) that is at least 25% lower
than the intelligence-adjusted expected score, as assessed by the WAIS-IV Information and
Vocabulary subtests. The study consists of a screening period, one-week single-blind,
placebo run-in phase, and a 12-week double-blind acute treatment phase (Phase I). Subjects
will be randomized 1:1 to rivastigmine transdermal patch 9.5mg/24 hours (10cm2) or matching
placebo. During Phase I, there will be an initial 4-week titration period followed by an
8-week continuation phase. Following the 12-week acute treatment phase, randomized patients
will continue in the double-blind phase (Phase II) for additional 14 weeks or until study
treatment period ends. Efficacy will be determined by comparing the proportion of patients
in each treatment group who are classified as responders at week 12. Secondary measure of
functional capacity assessing the impact of memory improvement on real-world functioning,
other measures of cognitive domains affected in TBI, namely attention, working and episodic
memory and executive functions, as well as measures of mood and quality of life will be
examined. Study findings will contribute to the body of evidence needed to establish
standards of care for Veterans with posttraumatic memory impairment and other cognitive
deficits.

Inclusion Criteria:

- Be a male or a female of any race

- Be outpatient Veterans residing in the community

- Be 19-65 years old at the time of inclusion

- Female patients of childbearing potential must have a negative pregnancy test at
baseline and must practice an acceptable method of birth control during the trial

- Satisfy the following diagnostic criteria:

- A history of previous head trauma(s) at least 12 months prior to study
enrollment as determined by TBI diagnostic assessment

- Closed head injury (non-penetrating) based on ICD 9 CM 10 diagnosis code 854.0
as determined by TBI diagnostic assessment

- Meet or exceed the modified ACRM criteria for Mild TBI as determined by TBI
diagnostic assessment

- Have a deficit in the area of verbal memory

- Have subjective memory impairment that was reported to be present from the time of
injury or shortly thereafter to be associated with brain injury

- Satisfy the DSM-IV-TR criteria for cognitive disorder not otherwise specified,
dementia due to TBI, or amnestic disorder due to TBI

- Demonstrate willingness to accept randomization

- Provide written informed consent to participate in the study

Exclusion Criteria:

- Have a medical condition that can interfere with the diagnostic process and the
assessment of clinical and mental status, or possibly endanger their health. Such
conditions include, but are not limited to:

- endocrinological

- neurological (including epilepsia)

- cardiovascular (including clinically significant bradyarrhythmia, resting heart
rate <50 without a or treating physician's approval)

- pulmonary, hematologic, hepatitis, and renal conditions

- significant laboratory abnormalities as determined by Study Chair

- Have a current diagnosis of any primary neurodegenerative disorder, including
Huntington's disease, Parkinson's disease, or DSM-IV-TR dementia (other than Dementia
Due to Head Trauma)

- Have suicidal ideation or have been judged to be a significant suicide risk

- Have a history of DSM-IV-TR substance (drug and/or alcohol) dependence disorder
within the last 5 years or a history of a substance abuse disorder within the past 6
months

- Have a DSM-IV-TR lifetime and current psychotic disorder (except lifetime depression
with psychotic features), bipolar disorder, or pre-TBI onset
attention-deficit/hyperreactivity disorder

- Have current PTSD symptoms that can bias or interfere with cognitive and clinical
assessments as determined by study site PI.

- Have demonstrated suboptimal effort on cognitive testing as defined by:

- TOMM raw score below 45 on either Trial 2 or the Retention Trial, or

- MSVT score of <=85% on any one of the Immediate Recall, Delayed Recall, or
Consistency indices

- Have demonstrated a lack of tolerability to rivastigmine treatment in the past or
severe reactions to other cholinesterase inhibitors as determined by the site
investigator

- Be taking medications that significantly affect cognitive functioning in TBI
population and/or may enhance the beneficial/adverse/toxic effect of rivastigmine or
vice versa. These compounds include, but are not limited to:

- centrally-acting anticholinergic drugs (e.g. atropine)

- other cholinesterase inhibitors (e.g. donepezil, galantamine)

- agents that augment cerebral catecholaminergic function (e.g) psychostimulants,
amantadine, memantine, selegiline, levodopa, etc)

- Treatment of non-exclusionary comorbid psychiatric symptoms with compounds that
include, but are not limited to antidepressants, anxiolytics, sedative-hypnotics,
anticonvulsants, and atypical antipsychotics will be permitted provided that:

- the site investigator, based on review of medical history, records and current
medications and in consultation with the Study Chair, concludes that the
agent(s) are neither cause(s) of nor significant contributor(s) to the potential
subject's memory impairment

- the dose of the agent(s) has been stable for the 3 months preceding study
participation

- the dose of the agent(s) remains stable, where clinically feasible, throughout
the study. For medications prescribed for non-exclusionary conditions on a PRN
basis, particularly when those medications include benzodiazepines,
sympathomimetics, antitussive agents or potentially sedating analgesics- every
use will be documented by the subject and will not be taken within 24 hours of
performing study-related cognitive testing (Appendix A: Exclusionary
Medications).

- Have been exposed to other cholinesterase inhibitors in the 30 days prior to
randomization

- Have a history of penetrating brain injury, cerebrovascular disease, cerebral
neoplasm, major brain surgery, or multiple sclerosis

- Have a significant visual or auditory deficit that may interfere with ability to
complete study assessments

- Have a limited ability to speak and read English

- Be participating in another clinical trial with active intervention